Traumatic brain injury (TBI) is reportedly the leading cause of death and disability among children and young adults (CDC Report, 2004). Among multiple sequelae, TBI results in three major pathologies: 1) cerebral edema which leads to a critical rise in intracranial pressure, 2) diffuse axonal injury which brings about disruption of neural circuits underlying cognitive and motoric behaviors, and 3) alterations in the brain's microcirculation that cause a persistent state of hypoperfusion and improper delivery of vital metabolites to neural tissue. Over 25 clinical trials aimed at the first two pathologies have been developed, none of which have been effective in the treatment for TBI. Therefore, novel studies leading to new clinical trials are necessary. To date no one has initiated a clinical trial addressing the third pathology, dysfunctional vascular reactivity following TBI. The present proposal provides rationale for proceeding towards a clinical trial by implementing novel strategies that aim to improve cerebral blood flow (CBF) and cognitive outcome following TBI. While our laboratory has published extensively on the role of endothelin-1 in mediating altered cerebral vascular reactivity after TBI, the cellular and molecular mechanism for this altered vasoreactivity remains to be elucidated. In addition the causal relationship between ET-1, altered vasoreactivity and functional outcome has not been established. This proposal addresses these issues by pharmacologic manipulation of the ET-1 system and calponin (Cp), a key element in vasoreactivity - the molecular events leading to vascular smooth muscle contractility and hence to vasoconstriction. The central hypothesis of this proposal is: TBI causes enhanced endothelin-1-mediated vasoconstriction and reduced CBF, which, in turn, exacerbates TBI-induced neuronal injury and cognitive deficits. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is the leading cause of death and disability amongst our youth and children. Further, it has been named as the signature injury in the War on Terrorism that, upon return of our men and women fighting in Iraq and Afghanistan, is projected to cost millions in patient care and rehabilitation costs. While TBI results in three major pathologies, including diffuse axonal injury, brain edema, and hypoperfusion of the brain's parenchyma, this proposal investigates novel methods to increase blood flow after injury by investigating the fundamental mechanism behind hypoperfusion. In doing so, the experiments in this proposal are designed to yield results that can quickly be translated into the clinical setting, thus off-setting the current potentially dismal outcome following exposure to TBI.